Treatment of skeletal muscle disorders with cyclobenzaprine

ABSTRACT

The present invention relates to a pharmaceutical composition providing a dosage unit of from 1 to 20 mg. of cyclobenzaprine and salts thereof useful as a skeletal muscle relaxant. It also relates to a method of treating muscular spasm and other similar muscular disorders associated with or caused by injury or arising spontaneously with no known cause by the administration of a pharmaceutical composition containing cyclobenzaprine or a salt thereof as one of the active ingredients.

United States Patent on Share on May 6, 1975 l l TREATMENT OF SKELETAL MUSCLE DISORDERS WITH CYCLOBENZAPRINE [75[ Inventor: Nathan Norman Share, Cote St.

Lue. Quebec. Canada Related US. Application Data [63] Continuation-impart of Ser. Nos |45 875 May 2L l97l abandoned. and Ser. No. 328.192. Jan. 3l. I973, abandoned,

[52] US. Cl. .t 424/330 [5l[ Int. Cl Afilk 27/00 [58] Field of Search 424/330 [56] References Cited UNITED STATES PATENTS 31154.64} 7/l96) Cope et al. i. 260/5708 TC OTHER PLlBLlCATlONS Parkes. Progress in Medicinal Chemistry; by Ellis & West l96l pp 72 and 92-94.

Primary E.\'uniiner-Stanley J4 Friedman Attorney. Agent. or Firm-James A Arno: Harry E, Westlake; Rudolph J Anderson. Jr

[57[ ABSTRACT The present invention relates to a pharmaceutical composition providing a dosage unit of from I to 20 mg of cyclohenzaprine and salts thereof useful as a skeletal muscle relaxant it also relates to a method of treating muscular spasm and other similar muscular disorders associated with or caused by injury or arising spontaneously with no known cause by the administration of a pharmaceutical composition containing cyclohenzaprinc or a salt thereof as one of the active ingredients.

5 Claims, N0 Drawings The present application is a continuationdn-part of copending application Ser. No. H5375. filed May 2]. l97l (now abandoned) and eopending application Ser. No. 32%.l92. filed Jan. 3], W73 (now abandoned).

The present invention relates to a pharmaceutical composition providing a dosage unit of from I to It) mg. of cyclobenzaprine and salts thereof useful as a skeletal muscle relaxant. It also relates to a method of treating muscular spasm and other similar muscular disorders associated with or caused by iniury or arising spontaneously with no known cause by the administrin tion of a pharmaceutical cotttpositiott containing cyclobenzaprine or a salt thereof as one of the active ingredients.

BACKGROLND Muscle spasm or spasticity and related clinical disorders involving muscle hyperactivity or increase in muscle tone affect a large section of the population. Such clinical disorders involving muscle hyperactivity include the spasticity of cerebral origin which may arise from brain injury or tumor. Another related disorder which is ofgreat importance especially in the treatment of children 6 to l4 years of age is cerebral palsy. Other clinical disorders involving tonic skeletal muscular hyperactivity are Parkinson's disease especially characterized by muscular spasticity and muscular rigidity and muscle spasm of traumatic origin including low-back and cervical spine syndromes. many orthopedic deformities. arthritic states. myositis'. whiplash injuries. frac tures. dislocations. cramps. sciatica and spinal cord injuries. At present a variety of medicinals are used in an attempt to relieve or correct the clinical disorders involving muscle hyperactivity including muscle spasm and spasticity and the pain associated therewith. But use ofthese various materials unfortunately is attended by concomitant side effects and toxicity which limit the usefulness of these medicinals. There is an unsatisfied need at the present time for a medication which has a high specific effect on muscle hyperactivity causing various clinical disorders when administered either by the oral or parenteral route and which at the same time has a minimum of side effects or contraindications.

DETAILED DESCRIPTION 1 iica cti or a pharmaceutically acceptable non-loxic salt thereof.

It is a further object of the present invention to de- \elop a method of effecting relaxation of skeletal muscles by the administration to the afflicted patient of htl from about .05 to about 4 tug/kg. of cyclobenzaprine or a pltarmaceutically acceptable non-toxic acid addition salt thereof.

Another object of the present invention is to provide a method for selectively reducing skeletal muscle tonic hyperactivity without effecting any loss in normal mus cle strength or causing any attendant sedation. behav ioral effects or other effects ordinarily associated with central nervous system depressants.

A still further object of the invention is to provide compositions in unit dosage form comprising from I to It) mg. of cyclobenzaprine or an acid addition salt thereof useful in the treatment of muscular spasm.

It is a further object of the present invention to provide methods and compositions for the alleviation of muscle tonic hyperactivity including muscular spasm. spasticity and rigidity without the attendant side effects of sedation. loss of normal muscle strength. depression. and other objectionable pharmacological effects. lt is a still further object ofthis present invention to prov ide a centrally acting agent comprising a unit dose of from 1-20 mg. of cyclobenzaprine which will selecti\ely reduce skeletal muscle tonic hyperactivity without causing central nervous system depression. These and other more specific objects will be apparent front the follow ing description and claims.

The present invention provides. in the form of a phar maceutical formulation ofcyclobenlaprine. a centrally acting agent which selecti\el v reduces skeletal muscle tonic hyperactivity without reducing normal muscle strength.

The compositions ofthe present invention are prefer ably presented for administration in unit dosage form as tablets. pills. capsules. powders. granules. sterile parenteral solutions or suspensions and the like. For preparing solid compositions such as tablets. the principal active ingredient is mixed with a pharmaceutical carrier. ie. conventional tableting ingredients such as corn starch. lactose. sucrose. sorbitol. talc. stearic acid. magnesium stearate. dicalcium phosphate. gums. and other pharmaceutical diluents. c.g.. water. to form a solid preformulation composition containing a homogeneous mixture ofcyclobenzaprine or a pharmaceuti cally acceptable non-toxic acid addition salt thereof admixed with the pharmaceutical carrier. When referring to these preformulation compositions as homogeneous. it is meant that the active ingredient. i.e.. cyclobcnzaprine or salt thereof. is dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets. pills. capsules. and the like. This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing front 1 to It) mg. of cyclobenzaprine or salt per unit dose. In a preferred mode of preparing the unit dose compositions of the invention. the cyclobenzaprine salt. preferably the hydrochloride salt. is mixed with a pharmaceutical carrier in a proportion of about one part of the active ingredient per hundred parts of foP mulation by weight. In this manner. tablets containing between 2 and It) mg. of cyclobenlaprine hydrochloride per tablet are prepared by mixing the appropriate amount of cyelobenzaprine hydrochloride with appropriate amounts of lactose or other suitable sugar. starch (preferably corn starch). and a salt of stearic acid. The mixture is suitably granulated and compressed into tablets containing between I and 20 mg. of the active ingredient per tablet. l hc tablets or pills of the mud composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action of the cyclobenzaprine or salt thereof. For example. the tablet or pill can comprise an inner dosage and an outer dosage component. the latter being in the form of an envelope 0\ er the former. The two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings. such materials including a number of polymeric acids or mivtures of polymeric acids with such materials as shellac. shellac and cctyl alcohol. cellulose acetate. and the like. A form which is in part enteric coated is particularly useful for the purpose of the present invention since the compositions of the present invention are characteriied by their rapid onset of action when ad ministered in conventional oral dosage form. e.g.. siniple compressed tablets and the like.

The liquid forms in which the novel composition of the present imention may be incorporated for administration include aqueous solutions. suitably flavored syrups. aqueous or oil suspensions. flavored emulsions with edible oils such as cottonseed oil. sesame oil. coconut oil. peanut oil and the like. as well as elixirs and similar pharmaceutical vehicles. Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth. acacia. alginatc. dcstran. sodium carboxymethylcellulose. methylcellulose. polyvinyl-py rrolidone. gelatin and the like.

The formulations of cyclobenzaprine and a pharma ceutically acceptable salt are normally administered orally. parenterally or rectally. Orally. they may be administered in tablets. capsules. suspensions or syrups. the preferred dosage form being a compressed tablet containing from l-ZtJ mg. of the active ingredient. for example. cyclobenzaprine hydrochloride per tablet, The optimum dosage depends of course on the dosage form being used and the type and severity of the condition being treated. In any specific case. the appropriate dosage selected ill further depend on factors of the patient which may influence response to the drug. for e\ample. general health. age. weight. etc. Age in partic ular appears to be a definite factor in selecting the appropriate dosage Thus. children appear to tolerate more of the drug on a mg lkg basis than normal adults. Although the optimum quantities of cyclobenzaprine or acid addition salt to be used in such manner depends on the particular salt employed in the particular type of muscular condition treated. oral dose levels of the preferred formulation in the range oftttlfi to 2 mg/kg. per day show e\ccllent effectiveness in adults. especially in the range oftll to tt-l mg .i'kg per day. ln children. on the other hand. the dose levels employed in \arious conditions range from tit)? to 5 mg. per day. The doses employed for cvample in the treatment ofchildren affected with cerebral palsy are in the order of approvimately 4 mg lkg. per day. Within this noted range. the dosage must. of course. be adjusted to the need of the patient taking into account the particular disease condition and other factors including general health. weight. etc. ('ornparative dosages are used in parenteral or rectal administration. The daily dosages are evpressed as mg. ofcyclobenzaprine base per kilogram of patient body weight per day.

till

ca v HC s cn n which is described in US. Pat. No. 3.454.643 ofArthur C. Cope and Edward L. Engelhardt. as a substance useful in tranquillizing animals or humans. and is incorporated herein by reference. The compound cyclobenzaprine is most easily administered in the form of a nontoxic acid addition salt. Such salts are prepared by methods known in the art. One such method utilized in the preparation of the preferred salt. cyclobenzaprine hydrochloride. is described in Example 1 ofthe abovenoted patent of Cope and Engelhardt and involves precipitation of the salt from a solution ofcyclobenzaprine in chloroform by saturating the solution with dry hydrogen chloride and cooling the solution to cause pre cipitation of solid cyclobenzaprine hydrochloride. Other salts. which are prepared in accordance with similar methods known to the art are those salts. the acid component of which is pharmaeeutically acceptable in the intended dosages. Such salts include those prepared from cyclobenzaprinc base and one of the group of acids including hydrochloric acid. hydrobromic acid. sulfuric acid. nitric acid. phosphoric acid. methane sulfonic acid. acetic acid. maleic acid. tartaric acid, lactic acid. salicylic acid and other similarly constituted acids used as the acid component of amine base acid addition salts for pharmaceutical administration.

The compositions of this invention. specifically cyclohenzaprine or a pharmaceutically acceptable nontovic acid addition salt thereof. preferably cyclobenza prine hydrochloride admixed with a pharmaceutically acceptable non-toxic carrier. are administered to patients suffering from skeletal muscle spasm or related muscular disorders to selectively reduce skeletal muscle tonic hyperactivity in the afflicted patient without reducing normal muscle strength. The compositions of cycloben/aprine are unusually specific in their muscle relasant properties and the administration of the compositions of cyclobenlaprine or a salt in either oral or injectable form results in an extremely rapid onset of action of the medication. The administration of the compositions of the present in ention is also surpris ingly free from any toxic reactions or side effects resulting from the medication. This is completely unexpected since the abo\e-cited patent mentions the use ofhigher dosage levels of the drug to quiet or tranquillize cattle. Remarkably. at the dosage levels recommended for the treatment of muscular spasm. there is a complete absence of any tranquilli7ing effect or other noticeable beha\ ioral effects.

The unusual and selective effect of cyclobenzaprine in reducing muscle hyperactivity associated with spasm has been demonstrated in test animals in comparison with other centrally acti\e agents reported to haye some muscle relaxant acti ity. In such tests cycloben/aprine is shown to be highly effective as a spasmolytic agent (reduces skeletal muscle hyperactivity) with no ataxia (failure of muscle coordination] at the cffecti e dose levels. Other compounds tested were not efl'ectoe at this level without displaying ataxia and other e i dence of loss of muscle strength,

The compositions of cycloben/aprine are administered in unit dosages of from l-Ztl mg. of cycloben/a prine present as an acid addition salt. e.g.. cycloben/aprine hydrochloride. Thus. in one preferred mode of treatment of muscular spasm. an average adult patient is treated by the daily administration of from 1 to 4-H) mg. tablets of cyelobemaprine hydrochloride at equally spaced intervals. If for some reason oral administration is not recommended. the patient suffering from muscular spasm or other related disorders is treated by the iniection. preferably by the intravenous route. of approximately 1 ml. of sterile aqueous solu tion containing from 1-20 mg. preferably about 10mg. of a salt of cyclobenzaprine. preferably eyclobcnzaprine hydrochloride. lf patient or physician preference dictates. other modes of administration. i.c.- intramus cular injection. rectal administration and the like may be employed. However. because of the extreme rapid onset of action in either the oral or intravenous mode of administration. there is rarely a need for other routes of administration.

The following are detailed examples showing the preparation of the pharmaceutical compositions ofthis invention. They are to be construed only as illustrations of said compositions and not intended as limitations thereof.

EXAMPLE I A lti-MILLIGRAM TABLET Ol" CYCLOBENZAPRINE Formula (ycloben/aprine hydrochloride Lactose L SP ('orn Starch l'SP Magnesium stearate l'SP A batch of 1000, l() mg. tablets of cyelobenzaprine is prepared by mixing the ingredients listed above as follows.

The cyclobenzaprine. lactose and a portion of the corn starch are mixed and granulated with a lU'fr' corn starch paste. The resulting granulation is sie ed and blended with magnesium stearate and the remainder of the corn starch. The resulting granulation is then compressed into tablets containing lt) mg. ofcyclobenza prine hydrochloride per tablet. Corresponding tablets containing respectively 2 mg.. 5 mg. and 2() mg. of cy clobenzaprine hydrochloride per tablet are prepared using the same procedure but \arying the amount ofcyclobenzaprine hydrochloride added to the mixture in the appropriate ratio.

EX MPLE 2 amount ofthe acid addition salt ofcyclobenzaprinc and hydrobromie acid.

The procedure of Example I is repeated using the same ingredients with the exception ofcyclobenzaprinc hydrochloride which is replaced with an equimolar amount ofthe acid addition salt ofcyclobenlaprine and sulfuric acid.

The procedure of Example 1 is repeated using the same ingredients with the exception ofcyclobemaprine hydrochloride which is replaced with an cquimolar amount ofthe acid addition salt ofcyclobenmprine and nitric acid.

The procedure of Example 1 is repeated using the same ingredients with the exception ofcyclobemaprine hydrochloride which is replaced with an equimolar amount ofthe acid addition salt ofcyclobenzaprine and phosphoric acid.

The procedure of Example I is repeated using the same ingredients with the exception ofcyclobenzraprine hydrochloride which is replaced with an equimolar amount of the acid addition salt otcyclobenzaprine and methane sulfonic acid.

The procedure of Example 1 is repeated using the same ingredients with the exception ofcycloben/aprinc hydrochloride which is replaced with an equimolar amount ofthe acid addition salt ofcyclobenzaprine and acetic acid.

The procedure of Example l is repeated using the same ingredients with the exception ofcyclobenzaprine hydrochloride which is replaced with an equimolar amount ofthe acid addition salt ofcyclobemaprine and maleic acid,

The procedure of Example I is repeated using the same ingredients with the exception of cyclobenzaprine hydrochloride which is replaced with an equimolar amount ofthe acid addition salt ofcyclobenzaprine and tartaric acid.

The procedure of Example I is repeated using the same ingredients with the exception ofcyclobemaprinc hydrochloride which is replaced with an cquimolar amount ofthe acid addition salt ofcyclobenzaprine and lactic acid.

The procedure of Example I is repeated using the same ingredients with the exception ofcyclobenzaprine hydrochloride which is replaced with an equimolar amount ofthe acid addition salt ofcyclobenzaprine and salicylic acid.

EXAMPLE 3 A ltl-MlLLlGRAM TABLET OF CYCLOBENZAPRINE Formula L'yclolwn/aprme hydrochloride Microcrystallme cellulose (orn starch ['SP agncsiuul stcarate l SP A batch of llltltl Ill-mg tablets ofcyelobenmprine is prepared by mixing the ingredients listed abo\e as follows.

The eyclobenzaprine. microcrystalline cellulose and a portion of the corn starch are mixed and granulated with a l0); corn starch paste. The resulting granulation is sieyed and blended with magnesium stearate and the remainder of the corn starch. The resulting granulation is then compressed into tablets containing ll) mg. ofcy clobenzaprinc hydrochloride per tablet. Corresponding tblets containing respectnely 2 mg. 5 mg. and 20 mg. f cyclobcnzaprine hydrochloride per tablet are preared using the same procedure but varying the nount of cyclobenzaprine lndroehloride added to the ristrue in the appropriate ratio.

EXAMPLE 4 INTRAVENOUS SOLI'TION ()F (YCLOBENZAPRINE HYDROCHLORIDE A solution containing Ill mg. ofcyclobciwaprine hyrochloride per milliliter of injectable solution is pre- .1red in the following manner. A mixture of III mg. of iclobenzaprine h droehloride and 50 mg. of Mannitol F is dissolved in sufficient water for injection to make ml. of solution. The solution is prepared and stored r such a manner that it is suitabl protected from the :Ieterious effects of the atmosphere. One method by hich this can be accomplished is by preparation and orage of the solution in an atmosphere of nitrogen. he resulting solution is sterilized by autoclaving. The wove example is given for a unit dose of cyclobenzarine but the same procedure may be appropriately nployed to make larger amounts of solution by utilizg the appropriate ratio of cyclobenzaprine hydroiloride. Mannitol NF and water for injection.

Other intravenous solutions having different concenations of cyclobcnzaprine are prepared by utilizin Z. or Ill mg. of cyelobenzaprine hydrochloride per ml. l' solution.

EXAMPLE 5 A FILM-COATED TABLET OF CYCLOBENZAPRINE Ingredients (yclobenzaprine hydrochloride 10 mg. I actose ltl'l mg. ('orn starch USP 32 mg. Magnesium stearate USP l mg.

Appropriate multiples of the above amounts are used required.

The c clobenzaprine. lactose. and a portion of the rrn starch are miwd and granulated with a 10% com arch paste. The resulting granulation is sieved. dried 1d blended with the remainder ofthe corn starch and re magnesium stearate. The resulting granulation is ten Compressed into tablets containing Ill mg. of c ohemaprine h drochloride per tablet.

FILM COATING Ingredients I 25 mg (ill H \dro\ \proptlccllulose litanium Dioxide Yellou Light Lemon l) \e l-ithanol Anh \drous Chlorol'orm .\'l

I 18 me.

it 5 mg.

(Hi l mg. 431K] ml 4] (It) ml 2.5 mg. 5 mg cloberi/aipflrie hydrochloride Lactose (om starch LSP Magnesium stearate 2.5 5st Ihll ll 4 10.0 I I ll.ll (HI I X What is claimed is:

l. A method for treating patients afflicted with disorders involving skeletal muscle hypertonic activity selected from the group consisting of muscle spasm. muscle spasticity. muscle rigidity or muscle splinting which comprises administering to said patient a therapeuti cally effective and safe dosage of cyclobenzaprine of the formula HHCH CH N or a pharmaceutically acceptable non-toxic acid addition salt thereof in an amount between 0.05 to 5 ni i z./l\'g./da of said cyclobenzaprine or salt to selectively reduce skeletal muscle hypertonic activity with out significantly reducing normal muscle strength or coordination.

2. A method according to claim I wherein the unit dosage administered is from l2tl mg.

3. A method according to claim 2 in which the cyelobenzaprine is administered orally.

4. A method according to claim 2 in which the cyclobenzaprine is administered parenterally.

5. A method according to claim 1 wherein the cyclobenzaprine is administered in the form of the hydrochloride. 

1. A METHOD FOR TREATING PATIENTS AFFLICTED WITH DISORDERS INVOLVING SKELETAL MUSCLE HYPERTONIC ACITVITY SELECTED FROM THE GROUP CONSISTING OF MUSCLE SPASM, MUSCLE SPASTICITY, MUSCLE RIGIDITY OF MUSCLE SPLINTING WHICH COMPRISES ADMINISTERING TO SAID PATIENT A THERAPEUTICALLY EFFECTIVE AND SAFE DOSAGE OF CYCLOBENZAPRINE OF THE FORMULA
 2. A method according to claim 1 wherein the unit dosage administered is from 1-20 mg.
 3. A method according to claim 2 in which the cyclobenzaprine is administered orally.
 4. A method according to claim 2 in which the cyclobenzaprine is administered parenterally.
 5. A method according to claim 1 wherein the cyclobenzaprine is administered in the form of the hydrochloride. 